Amino chromanes



Patented Sept. 12, 1944 AMINO CHROMANES Otto Hromatka, Darmstadt, Germany, assignor to Merck & Co. Inc., Rahway, N. J., a corporation of---New Jersey No Drawing. Original application December 2,

1939, Serial No. 307,265. Divided and this application May 27, 1941, Serial No. 395,444. In Germany January 31, 1939 15 Claims.

This invention relates to organic chemical compositions and compounds of the chromane and substituted chromane type, to intermediates for the production of such compounds, and to processes for their production.

Such chromanes and-substituted chromanes exhibit the biological action of the tocopherols, i. e., vitamin E.

The synthesesof such compounds now'available involve the use of hydroquinones asstarting materials. For instance, one of the known processesinvolves the use of pseudocumohydroquinone (3,6-dihydroxy-1,2,4-trimethyl benzene) with phytol or phytol derivatives. Pseudocumohydroquinone is' a difiicultly obtainable substance, and the processes now known forits production are impracticable and result in only verysmall yields.

When xylohydroquinone is reacted with'phytol or phytol derivatives a mixture of several substances is obtained in addition to the desired hydroxy chromane, such as condensation products formed by the substitution of two phytyl radicals in the molecule.

According to the determinations of Karrer and his co-workers (Helv. Chim. Acta,vol. 21, pages 823, 1234; vol. 22, page 661) such'by-products can only be separated with great difficulty from the reaction product'desired.

It will be apparent then that the syntheses of the tocopherols now'available are unsatisfactory from a practical point of view, because of the difficulty of obtaining the starting materials required in the various reactions.

I have now discovereda new synthesis for these important biologically active products, which synthesis avoids the use of hydroquinones as starting materials. Myzprocess involves the use of G-hydroxybenzenes of the formula wherein R may be hydrogen or methyl, one R ortho to the hydroxyl group always being hydrogen, andR may be a group capable of conversion to a hydroxyl'group as starting material. These compounds are condensed with dienes such as phytadiene, dimethylbutadiene, .isoprene, etc.,

or with allylic halides such as, for example, phytyl bromide, dimeth-yl allyl bromide, etc., or

' substituted 6-aminochromane thus obtained by the corresponding alcohols,.-such as phytol, for- Where 3-aminobenzenes are employed as starting material, the amino group is preferably protected during the condensation reaction, as for example, by means of acylation,

ester, or formicacid, no esterification of the phenolic hydroxyl group takes :place, but merely the complete formylation .of the amino group.

The amino group can also be protected by benzylation. The groups employed for blocking or protecting the amino group may be cleaved off by hydrolysis, inthe case of acyl compounds,

preferably by acidoompounds; in those caseswhere the aminogroup is protected by benzylation, the benzyl radical may be split off as toluene by catalytic hydrogenation.

Where S-nitrobenzenes are employed as starting materials in the reaction, the nitrogroup is converted to an amino group. The products of the reaction between v3enitrobenzenes and the phytol or phytol derivatives, or allyl halides are worked up in such a manner that residues of the 3-nitro-6-hydroxybenzenes used may be eliminated by means of aqueous alkalis. Because of the presence of the nitro group, the acid nature of the phenolic hydroxyl group appears tobe intensified, and. therefore these compounds can be shaken out even with dilute or weakly alkaline materials, for example, with soda solution, and the fi-nitrochromane derivatives, which are easily soluble in alcohol, can be separated from the con' version productsthat are insoluble in alcohol,

andcan be purified by distillation under high vacuum. It, is also. possible to catalytically hydrogenatethe alcoholic solution of the unpurified substituted 6-nitrochromane, and then purify the chromatographing its benzine solution on aluminum oxide, or by the salt formation.

especially formylation. If iormylationis carried out by heating the selected benzene with formic acid.

It is also possible to isolate the obtained 6- aminochromane derivatives by means of their salts with organic dibasic acids such as oxalic acid, d-tartaric acid or malic acid in the molecular proportion of one molecule of the 6-aminochromane and half. a molecule of the acid. These well crystallising salts are sparingly soluble in alcohol.

The 3-nitro-6-hydroxybenzenes which may be employed as starting materials for the processes of my invention are stable compounds and are not susceptible to atmospheric oxygen. They are readily soluble in the organic solvents used in the condensation, as for example, benzine or in formic acid. The 6-nitrochromanes obtained in the condensation are likewise not subject to oxidation. Furthermore, they can be' readily distilled under high vacuum without decomposition and can thus be easily separated from any by-products. a

The 3-aminochromanes obtained according to my invention may be converted to 6-hydroxychromanes by diazotizing and. boiling, even though these compounds have very weakly basic properties, their salts being usually hydrolyzed completely, with water, and the base being shakenout with ether. Diazotization may be successfully carried out even in spite of the very high general susceptibility to oxidation of amines of this, type. I have found that on boiling an aqueous 'alcoholic solution of the .diazonium salts, there occurs chiefly a combination with thefhydroxyl group instead of with the originally presentamino group, and not, as is usually thecase when boiling alcoholic solutions of diazonium salts, a combination with an OC2H5 group or with a hydrogen atom.

The 6-aminochromanes obtained as intermediates in the present process can also be converted into G-hydroxy-chromanes, i. e., a-tOCO- pherol or its homologs, byoxidation, hydrolysis of the quinonamines thus obtained, and hydrogenation of thequinones. The reduction or hydrogenationmay, beeffected with zinc dust or withjotherusual reducing agents, in presence of copherol, as determined by the absorption spec-.

trum, by formation of the allophanate derivations described herein in terms of 1,2,4-trimethyl-6-hydroxy-3-aminobenzene and phytol.

It will be apparent that the reactions illustrated are analogous for the other fi-hydroxybenzenes substituted at position 3 by a group capable of conversion to a hydroxyl group.

In thefollowing examples there are given detailed descriptions of the various reactions referred to herein. However, it will be apparent to those skilled in the art that various modifications may be made therein without departing from the spirit and scope of the invention herein described and claimed.

7 Example I 120 gms. of 3 -amino-6-hydroxy-1,2,4-trimethylbenzene (obtained by the catalytic reductionofthe nitroso compound from 1,2,4-trimethyl-3-hydroxybenzene described by Nietzky and Schneider, B. 27, 1431 [1894]) is heated with 240 cc. of 99% formic acid for 3 hours under refluxing at 100 C. The formyl compound crystive, and by thehigh vitamin E activity which it exhibits on animals.

Whenhigher or. lower homologs of 3-nitroor 1 3-amino-1,2A-trimethyl-fi-hydroxybenzenes' are employed, the resulting product is a corresponding higher or lower homolog of d,l-- tocopherol. V r

The products produced according to my in- Iventio'gn exhibit a high degree of vitamin E activity. Furthermore, the G-acylaminochromanes. and the free G-aminochromanes which can be used'advantag'eously in the form of their crystalline salts, also exhibit a high degree of vitamin E activity; d,l-;a-tocopherol itself does not formcrystalline salts.

The aminochromanes have, the further advantage over d,l-a-tocopherol and is homologs in that the latter compound is easily oxidizable, whereas the aminochromanes especially in form of their salts, are not sen-sitive to atmospheric oxygen. 7

The following flow sheet illustrates the reactallizes out from the solution on cooling and is filtered with suction. By evaporating the mother liquors under vacuum and again treating the residue with formic acid, an almost theoretical yield of 3-formylamino-6-hydroxy-1,2,4-trimethyl-benzene may be obtained.

7.2 gms. of 3-formylamino-6-hydroxy-1,2,4- trimethylbenzene, 12.0 gms. of phytol, and 60 cc. of 99% formic acid are boiled for 5 hours with refluxing. On cooling, the solution is highly diluted with water and the separated oil is extracted with ether. The ether solution is shaken well with water'and with an aqueous N-2 sodium hydroxide solution until the liquors remain highly alkaline using phenolphthalein as an indicator. The ether solution is driedand evaporated. The oily residue is dissolved in petroleum ether and chromatographed on aluminum oxide. The chromatogram is developed with an abundantamount of petroleum ether. A small amount of a colored compound is retained in the upper end of the column, then'a wide zone fol- V lows containing the desired chromane which is bounded again in the lower part of the column I by a narrow zone of a colored compound. Some unconvertedphytol and its ,traiisformationproducts are notabsorbed. The wide, colorless zone is extracted with a mixture ori parts ether and 1 part methanol and the solution obtained is evaporated to dryness. I 2,5,7,8- tetramethyl-2- (4',8',12' trimethyl tridecyl) 6 formylaminochromane is obtained as acolorless, viscous oil, which crystallizes slowly.

The same chromane may be obtained by the conversion of an equivalent amount of 3-amino- G-hydroxy-1,2,4-trimethylbenzene, in place of 3- formylamino-G-hydroxy-1,2,4- trimethylbenzene, with phytol arid formic acid. The working up is effected in the same Way.

6.0 gmS. of 2,5,7,8-tetramethyl-2-(4',8',12-trimethyltridecyl)-6-iormylaminochromane is dissolved in 120 cc. of warm absolute alcoholic hydrochloric acid, treated with 26 cc. of water and boiled for an hour'under refluxing. The hydrochloride of 2,5,7,8-tetramethyl-2-(4',8,12'- trimethyl-tridecyl) -6 aminochromane crystallizes out on cooling. The yield amounts to 5.7 gms. or 93% that of theory. The compound melts at about 158-160" C; and has been found. to exhibit vitamin-E activity in tests with animals. Other hydrohalides of the amino compound may also be produced in the same manner.

Instead of chromatographing the 2,5,7,8-tetramethyl 2 (4',8',12' trimethyl tridecyl) 6 formylaminochromane it is possible to treat the crude product in the described manner with aqueous-alcoholic hydro-chloric acid. The solution is highly diluted with water and the oil is extracted with ether. The ether solution is shaken with a cold soda solution and evaporated to dryness. The residual crude 2,5,7,8-tetramethyl-2(4',8', l2'-trimethyl-tridecyl) 6 aminochromaneis treated with the calculated amount of oxalic acid in alcoholic solution. The crystallized oxalic acid salt has the composition Cz9H51ON. C2H2O4 and melts at 153 C. p

0.932 gm. of 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl) -6-aminochromane hydrochloride is dissolved in 8 cc. of absolute alcohol and treated rates out. This is taken up with petroleum ether,.

chromatographed and developed with petroleum ether. The colorless, wide zone bordered with two yellow zones is extracted with ether-methanol (9:1) The residual oil, on evaporating the solvent, is dJ-a-tocOphElOl.

Example II 18,8 gms. of 3-amino-6-hydroxy-1,2,4-trimeth-' ylbenzene hydrochloride. (obtained by the catalytic reduction of the 3-nitroso compoundirom 1,2,4-trimethyl-3-hydroxy-benzene described by- Nietzky and Schneider, B. 27,1431 (1894) is suspended in 100 cc. of ice water and treated with 13.6 gms. of crystallized sodium acetate, containing 3 molecules of water of crystallization. The solution is shaken for an hour on the addition of 20.6 gms. of acetic anhydride. The mixture becomes solid after a short time, but itIis possible toshake it further after, energetic stirring. The.

crystals are. filtered with suction and dried. The yield of 3-acetamino-6-hydroxy 1,2, Ltrimethylbenzene is almost quantitative. Melting point 185-186 C.

To a solution of 7.5 gms. of phytyl bromide in cc. benzene isadded 3.86 gms. of 3-acetamino- 6-hydroxy-1,2,4-trimethylbenzene and 2.0 gms. of anhydrous zinc chloride. The mixture is refiuxed until the evolution of hydrogen bromide. is complete. -0n cooling, the benzene solution is decanted, washed with ammonia, 2.0 N- sodium hydroxide, and water, dried with potassium carbonate and evaporated. The residue is dissolved in petroleum ether and chromatographed on aluminum oxide. The same chromatogramis obtained, as in the case of the corresponding formyl 3 compound in Example I. The 2,5,7,8-tetramethyl-2-(4';8,l2',-trimethyl-tridecyl) 6 acetamino chromate is obtained as a viscousoil, which crystallizes slowly. This compound is saponified in an aqueous-alcoholic solution of hydrochloric acid and is worked up to d,l-a-tocopherol as in Example I. I

Example III 6.0 gms. of 'phytol are converted to phytyl bromide by means of phosphorus tribromide. (Analogous to the method of preparation of tetrahydrofarnesyl bromide described by Fischer, An. 475, 183 (1929).)

7.5 gms. of phytyl bromide are dissolved in 100 cc. of benzene and added to 3.6 gms. of 3'-formylamino-6-hydroxy-1,2,4-trimethylbenzene and 1.8 gins. of anhydrous zinc chloride. Themixture is boiled for two hours under refluxing. The formylamino hydroxytrimethylbenzene solves quite rapidly and hydrogen bromide is evolved. On cooling, the benzene solution is decanted from the liquid zinc chloride and diluted with ether. This solution is washed in a separating funnel consecutively with ammonia, 2.0 N

ample I, or according to the procedure described in thefollowing example.

Example IV 0.932 gm. of 2,5,7,8-tetramethyl-2-(4',8',l2'-

trimethyl-tridecyD-G aminochromane hydrochloride is dissolved in 7 cc. of warm absolute alcohol, treated with 20 cc. water, whereby the. solution becomes turbid. 0n the addition of "6'- cc. of liquor ferri sesquichlorati DAB. '6, the mixture is heated for 1.5 hours on the steam bath. A' brownoil is formed,.which is extracted with ether. the ether solution is reducedin aqueous alcoholic hydrochloric acid with an excess of zinc dust,

and the colorless solution is diluted with Water.

The d,'l.-a-tocopherol which separates out is dissolvediin petroleum ether and purified" by chromatographing on aluminum oxide. The com:-

pound is extracted with ether-methanol andyields as'a residue, d,l-a,-tocopherol.

ExampleV 6.6 gms. of 3 formylamino-2,4-dimethyL6-hyq droxybenzene (prepared by boiling B-amino-ZA- dimethyl-6 hydroxybenzene with formic acid) and 12' gms. of phytolare'boiled.v for. six hours 5' dis The residue obtained on evaporation of' refluxing for one hour.

under refluxing in 60 cc. of 99% formic acid.

After cooling, the mixture is diluted with much water and the oil which separates out is extracted withethelz, The ethereal solution is shaken out first with water and then with 2 N aqueous sodium hydroxide, until the solution remains strongly alkaline to phenol-phthalein. 'The ether solution is dried with magnesium sulfate 'and evaporated. The oily residue is dissolved in 200 cc. of ordinary benzine, chromatographed'on aluminum oxide, and developed with ordinary benzine. Narrow, colored zones atthe' upper and at the lower ends of the column are removed. The colorless, wide middle zone is eluted with a mixture of 9 parts or ether and 1 part of methanol, and the solution is evaporated. 2,5,7-trimethyl 2-(4',8',12 trimethyl tridecyl) -"6 formylaminochromane is obtained in the form of a colorless oil. i i

- The same compound can be obtained with an equally good yield if instead of B-formylamino- 2,4-dimethyl-6-hydroxybenzene the equivalent quantity of 3-amino-2,4-dimethyl-6-hydroxybenzene is treated with phytol in formic acid under the same conditions. i

. gms. of 2,5,7-trimethyl-2 (4',8',12-trimethyl-tridecyl) -6-formylaminochromane is dissolved in 2.00 cc. of alcoholic hydrochloric acid, mixed with cc. of water, and boiled under On cooling and careful addition of water, the hydrochloride of 2,5,7-trimethyl-2- (4' ,8,12'-trimethyl-tridecyl) -6-aminochromane crystallizes out. The compound melts at about BIO-142C. The yield is almost quantitative. The compound shows strong vitamin-E action. (Administration of one dose of 3 mg. is effective with 60% of the rate used.) Other hydrohalides of the amino compound ma also be produced in the same manner.

In the same manner as described in Example I it is possible to hydrolize the crude 2,5,7-tri- V methyl-2(4,8,12'-trimethyltridecyl) -6-formyllow crystals (M. P. 147 C.) By 'diazotizing and boiling of the 2,5,7-tr1- methyl-2- (4,8',12-trimethyl-trldecyl) -6-amino-l chromane, 2,5,7-trimethyl-2-i4',8,12-trimethyltridecyl) 6hydroxychromane is obtained.

Exam le VI 6.6 'gms, of 3-formylamino-1,4-dimethyl-6-hy-' droxybenzene, (prepared from 3-amino-1,4-dimethyl-S-hydroxybenzene, by boiling with formic acid), 12 gms. of phytol, and 60 cc. of 99% formic acid are boiled under refluxingfor six hours in a current of nitrogen. The working up proceeds in the same manner as in Example V and gives 2,5,8-trimethyl-2- (4,8,l2' -trimethyl-tridecyl) -6- formylaminochromane as a colorless, viscous oil.

'Saponification of this compound with aqueousalcoholic hydrochloric acid is carried out at a boiling temperature under nitrogen. The hydro-.

chloride of 2,5,8-trimethyl-2-(4,8,12-trimethyltridecyl)-fi-aminochromane separates out as an oil and is purified by dissolving andreprecipitating from alcoholic' hydrochloric acid. Other hydrohalides of the amino compound may also be produced in the same manner.

The base shows vitamin-E activity. One dose of 10 mg. of the base is effective with 60% of the rats used in the animal test. With p-nitrobenzoylchloride in pyridine solution the base gives crystalline 2,5,8-trimethyl-2-(4',8',12'-trimethyliridecyl) -G-p-nitrobenzaminochromane, M. P, 80

The conversion of the amino group into the hydroxyl group is carried out by diazotizing and boiling, and yields d,l-p-tocopherol.

Example VII is taken up in ether. The ether solution is drawn oiT and treated with dilute sodium hydroxide solution until the solution turns an orange-red color (phenolphthalein-alkaline reaction). After separation of the layers the ether solution is dried and evaporated.

The residue is dissolved in a little alcohol, in which the substituted nitrochromane is soluble, whereas a few drops of the oil remain undissolved. The solution is evaporated to dryness and the residue is distilled under vacuum at 0.05 mm.

and in air bath temperature of 170-200 C. 2,5,7- trimethyl-2- (4',8',l2'-trimethyl-tridecyl) -6 n l trochromane in the form of a yellow oil is obv tained.

2.17 gms. of 2,5,7-trimethyl-2-(4',8',12'-trimethyl-tridecyl)-6-nitrochromane is dissolved in cc. of alcohol, treated with 1 cc. of hydrochloric acid (d. 1.19) and after the addition of 2 gms. of 10%.palladiumcharcoal, ishydrogenatecl catalytically. When the calculated amount of hydrogen is absorbed, the solution is filtered from.

the catalyst and evaporated under vacuum. The crystallized residue is 2,5,7 -trimethyl-2- (4',8,l2- trlmethyl-tridecyl) -6-aminochromaneh y d r o chloride and is recrystallized from dilute alcoholic hydrochloric acid. r

2,5,7-trimethyl-2- (4,8,12'-trimethyl-tridecyl) S-p nitrobenzaminochromane, obtained from the base with p-nitrobenzoyl chloride in a pyridine solution shows a melting point of about 147 C.v

Example VIII dilute hydrochloric acid. The ether solution is dried and evaporated. The further working up to 2,5,7-trimethyl-2-(4',8,12-t rim e t h y l-tridecyl) -6-amino-chromane takes place as described in Example I.

Where-the term amino radical is used in the appended claims it is intended to cover the radical NHz and substituted amino radicals.

This application is a division of my application O Ser. No. 307,265, filed December 2, 1939.

1 claim: 1. Salts of compounds of the formula R CH2 R2 5B: R R o R wherein R is selected from the group consisting of hydrogen and methyl radicals, R is an alkyl radical, and R is an amino radical.

2. Salts of compounds of the formula wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical, and R is an amino radical, with organic dibasio acids.

3. hydro-halide salts of compounds of the formula wherein R is selected from the group consisting of hydrogen and methyl, R is an alkyl radical, and R is an amino radical.

4. The hydrochloride of 2,5,7,8-tetramethyl-2- (4 ,8 ,12' -trimethyl-tridecyl) -6-amino-chromane.

5. The hydrochloride of 2,5,7-trimethyl-2- (4 ,8,12'-trimethyl-tridecyl) -6-amino-chromane.

6. The oxalic acid salt of 2,5,7,8-tetramethyl-2- (4',8,12-trimethyl tridecyl) -6-amino-chromane.

7. The process comprising condensing a compound of the formula wherein R is selected from the group consisting of hydrogen and methyl, one R ortho to the hydroxyl being hydrogen, and R is an amino radical, with a substance selected from the group consisting of aliphatic a-gamma-dienes, gammaalkylated allyl halides, and gamma-alkylated allylic alcohols, in the presence of an acidic substance, and forming a hydrohalide of the resulting G-amino-chromane.

9. The process comprising condensing a compound of the formula where R is selected from the group consisting of hydrogen and methyl, one R ortho to the hydroxyl group being hydrogen, and R is an amino radical, with a substance selected from the group consisting of aliphatic alpha, gamma-dienes, gamma-alkylated allyl halides, and gamma-alkylated allylic alcohols, in the presence of an acidic substance, and forming an organic dibasic acid salt of the resulting fi-amino-chromane.

10. The process comprising condensing a 3- amino-G-hydroxy benzene in which one position ortho to the hydroxyl group is unsubstituted, with phytol, in the presence of an acidic substance, and forming a salt of the resulting G-amino-chromane.

11. The process comprising condensing a 3- amino-G-hydroxy-benzene in which one position ortho to the hydroxyl group is unsubstituted, with phytol, in the presence of an acidic substance and forming a hydrohalide of the resulting fi-amino-chromane.

12. The process comprising condensing a 3- amino-6-hydroxy benzene in which one position ortho to the hydroxyl group is unsubstituted, with phytol, in the presence of an acidic substance, and forming an organic dibasic acid salt of the resulting 6-amino-chromane.

13. The process comprising condensing a 3- amino-G-hydroxy-1,2,4-trimethyl benzene with phytol in the presence of an acidic substance, and forming the hydrochloride of the resulting 2,5,7,8- tetramethyl-2-(4,8,l2'-trimethyl tridecyl) 6- amino-chromane, by treatment thereof with hydrochloric acid.

14. The process comprising condensing a 3- amino-2,4-dimethyl-6-hydroxy benzene with phytol in the presence of an acidic substance, and forming the hydrochloride of the resulting 2,5,7- trimethyl-Z (4',8',12' trimethyl tridecyl) 6- amino-chromane, by treatment thereof with ydrochloric acid.

15. The process comprising condensing a 3- amino-G-hydro-xy-1,2,4-trimethyl benzene with phytol in the presence of an acidic substance, and forming the oxalate of the resulting 2 ,5,'7,8-tetramethyl 2 (4',8',12' trimethyl tridecyl) 6- amino-chromane, by treatment thereof with oxalic acid.

OTTO HROMATKA.

CERTIFICATE. or CORRECTION. Patent No. 2, 58,2 7. September 12-, 19M.-

OTTO HROMATKA;

It is hereby certified that error appears in the printed s ecification of the above numbered patent requiring correction as follows Page 2, first column, 1i'ne'70, for the words "andis" read- -'-and its-; page 5, second column, line 17, for "'chromate" read --chromane--; page L .,-f1rst column, line 57, for "rat e read -rats; page 5','first co1umn, line 21 claim 5,

for "hydro-halide" read --Hydroha1id'e--; and that the said Letters Patent should be read'with' this correction thereinthat' the same may conform to the record of the case in the Patent Office.

Signed and sealed this 2nd day of January, A. D. 19150 Leslie Frazer (Seal) Acting Commissioner of Patents. 

